A Phase I/II Study of MLN8237, an Oral Selective Small Molecule Inhibitor of Aurora A Kinase, in Children With Relapsed/Refractory Solid Tumors
- To estimate the maximum tolerated dose and recommended phase II dose of Aurora A kinase
inhibitor MLN8237 administered once daily or twice daily in pediatric patients with
relapsed or refractory solid tumors (except CNS tumors) or acute lymphoblastic leukemia
(ALL). (ALL closed to accrual as of 02/18/10)
- To evaluate the toxicity of this drug in these patients.
- To characterize the pharmacokinetics of this drug in these patients.
- To determine the antitumor activity of this drug in these patients. (Phase I)
- To determine the efficacy of this drug, using the once daily dosing schedule, in these
patients. (Phase II)
- To explore the relationship between polymorphic variations in the
UDPglucuronyltransferase gene UGT1A1 and exposure to MLN8237.
- To assess two common polymorphic variants in the Aurora A kinase gene (Phe31Ile and
Val57Ile) thought to potentially influence tumorigenesis.
- To examine the relationship between Aurora A expression status and response to Aurora A
OUTLINE: This is a multicenter phase I, dose escalation followed by a phase II study.
Patients are stratified according to diagnosis (solid tumors vs neuroblastoma vs acute
lymphoblastic leukemia). (Acute lymphoblastic leukemia closed to accrual as of 02/18/10)
Patients receive oral Aurora A kinase inhibitor MLN8237 once or twice daily on days 1-7.
Courses repeat every 21 days for up to 24 months in the absence of disease progression or
Whole blood samples are collected from all patients for genotyping for polymorphisms in
UGT1A1 enzymes and polymorphisms in the Aurora A kinase gene. For patients in the phase II
portion of the study, previously preserved tumor tissue blocks and bone marrow or peripheral
blasts are evaluated for Aurora A kinase protein using IHC, mRNA expression, and gene
amplification using FISH or quantitative PCR. Bone marrow is also obtained for FAB
morphology, immunophenotyping, and cytogenetics. Blood samples are also collected
periodically during the first course of therapy for pharmacokinetics studies.
Primary Purpose: Treatment
Maximum tolerated dose and recommended phase II dose of Aurora A kinase inhibitor MLN8237 administered once daily or twice daily (Phase I)
Yael P. Mosse, MD
Children's Hospital of Philadelphia
United States: Federal Government
|Children's Hospital of Philadelphia||Philadelphia, Pennsylvania 19104|
|Children's Hospital of Orange County||Orange, California 92668|
|Children's National Medical Center||Washington, District of Columbia 20010-2970|
|Children's Hospital and Regional Medical Center - Seattle||Seattle, Washington 98105|
|Children's Memorial Hospital - Chicago||Chicago, Illinois 60614|
|St. Jude Children's Research Hospital||Memphis, Tennessee 38105-2794|
|Cincinnati Children's Hospital Medical Center||Cincinnati, Ohio 45229-3039|
|Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center - Dallas||Dallas, Texas 75390|
|Baylor University Medical Center - Houston||Houston, Texas 77030-2399|
|Indiana University Melvin and Bren Simon Cancer Center||Indianapolis, Indiana 46202-5289|
|Dana-Farber/Harvard Cancer Center at Dana-Farber Cancer Institute||Boston, Massachusetts 02115|
|C.S. Mott Children's Hospital at University of Michigan Medical Center||Ann Arbor, Michigan 48109-0286|
|Masonic Cancer Center at University of Minnesota||Minneapolis, Minnesota 55455|
|Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis||St. Louis, Missouri 63110|
|Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center||New York, New York 10032|
|Knight Cancer Institute at Oregon Health and Science University||Portland, Oregon 97239-3098|
|Children's Hospital of Pittsburgh of UPMC||Pittsburgh, Pennsylvania 15213|
|UAB Comprehensive Cancer Center||Birmingham, Alabama 35294|